Abstract
All cryptochromes are currently classified as flavoproteins. In animals their best-described role is as components of the circadian clock. This circadian function is variable, and can be either light-dependent or -independent; the molecular origin of this difference is unknown. Type I animal cryptochromes are photoreceptors that entrain an organism’s clock to its environment, whereas Type II (including mammals) regulate circadian timing in a light-independent manner. Here, we reveal that, in contrast to Type I, Type II animal cryptochromes lack the structural features to securely bind the photoactive flavin cofactor. We provide a molecular basis for the distinct circadian roles of different animal cryptochromes, which also has significant implications for the putative role of Type II cryptochromes in animal photomagnetoreception.
Highlights
Circadian rhythms manifest in almost all organisms and control a wide range of physiological processes
Type II cryptochromes are expressed without bound flavin adenine dinucleotide (FAD)
The circular dichroism (CD) spectrum of DmCRY in the visible region shows a strong FAD signal, which is diagnostic of the flavin being bound in the chiral environment of the protein (Fig. 1d, inset)
Summary
Circadian rhythms manifest in almost all organisms and control a wide range of physiological processes. We hypothesize that a major contributing factor to the contrasting roles of Type I and Type II animal CRY is the differential binding of FAD. Such differential binding is likely to act in concert with, or even directly influence, other important factors such as the different interaction partners and genetic networks that exist within the clock of invertebrates and vertebrates. To test this hypothesis, we conducted a combined experimental/computational study of FAD-binding to typical Type I and Type II CRY
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